The Receptor Tyrosine Kinase MuSK Is Required for Neuromuscular Junction Formation In Vivo

TLDR

Neuromuscular synapse formation relies on inductive interactions between motor axons and muscle cells, yet the receptors and signaling pathways mediating these interactions remain unidentified. Mice lacking MuSK, a postsynaptic receptor tyrosine kinase, were generated to test its role in synapse formation. MuSK-deficient mice fail to form neuromuscular synapses, indicating that MuSK, activated by the nerve-derived signal agrin, orchestrates postsynaptic organization, synapse‑specific transcription, and presynaptic differentiation.

Abstract

Formation of neuromuscular synapses requires a series of inductive interactions between growing motor axons and differentiating muscle cells, culminating in the precise juxtaposition of a highly specialized nerve terminal with a complex molecular structure on the postsynaptic muscle surface. The receptors and signaling pathways mediating these inductive interactions are not known. We have generated mice with a targeted disruption of the gene encoding MuSK, a receptor tyrosine kinase selectively localized to the postsynaptic muscle surface. Neuromuscular synapses do not form in these mice, suggesting a failure in the induction of synapse formation. Together with the results of an accompanying manuscript, our findings indicate that MuSK responds to a critical nerve-derived signal (agrin), and in turn activates signaling cascades responsible for all aspects of synapse formation, including organization of the postsynaptic membrane, synapse-specific transcription, and presynaptic differentiation.